prediction of oesophageal varices and its grades using the...

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EUROPEAN ACADEMIC RESEARCH

Vol. V, Issue 1/ April 2017

Impact Factor: 3.4546 (UIF)

DRJI Value: 5.9 (B+)

Prediction of Oesophageal Varices and Its Grades

Using the Glycated Albumin to Glycated

Haemoglobin (GA/HbA1c) Ratio in Egyptian

Patients with Liver Cirrhosis

NOHA A. ELNAKEEB

EMAN EL-SAYED1

HOSAM S ELBAZ Department of Internal Medicine

Faculty of Medicine, Ain Shams University, Cairo, Egypt

AMIRA I HAMED

Department of Clinical Pathology

Faculty of Medicine, Ain Shams University, Cairo, Egypt

Abstract:

Many non-invasive methods have been proposed to evaluate the

presence and the grade of oesophageal varices (O.Vs). This work aimed

to assess the value of GA/HbA1c ratio as a non-invasive predictor of

OV and its grading. The study included 45 patients with established

liver cirrhosis and oesophageal varices (subdivided into 3 groups

according to the O.Vs grade), and 15 non cirrhotic patients as a control

group. The history, clinical examination, laboratory investigations,

ultrasound examination and Upper Gastrointestinal Endoscopy were

done for all subject & GA/HbA1c ratio was calculated. There was a

highly significant difference between patient and control, and between

different patients’ subgroups as regard the GA/HbA1c ratio and there

was a high positive correlation between the GA/HbA1c ratio and grade

of OVs in all patients’ subgroups. These findings are suggestive that

the increased GA/HbA1c ratio may be considered as a predictor for

presence of O.Vs and its grade.

1 Corresponding author: [email protected]

Noha A. Elnakeeb, Eman El-Sayed, Hosam S Elbaz, Amira I Hamed- Prediction of

Oesophageal Varices and Its Grades Using the Glycated Albumin to Glycated

Haemoglobin (GA/HbA1c) Ratio in Egyptian Patients with Liver Cirrhosis

EUROPEAN ACADEMIC RESEARCH - Vol. V, Issue 1 / April 2017

376

Key words: Glycated albumin, HbA1c, non-invasive predictors,

oesophageal varices.

INTRODUCTION:

According to the latest WHO data published in January 2015,

Liver cirrhosis Deaths reached about 41.4 thousand patients

representing the third leading cause of death in Egypt (WHO:

Egypt Health profile, 2015). Portal hypertension is a major

complication of liver cirrhosis and can be a direct cause of

variceal haemorrhage and of bleeding-related deaths.

The upper gastrointestinal endoscopy (UGE) is still the

gold standard method to diagnose early oesophageal varices

and its bleeding and further complications (Garcia-Tsao et

al., 2007). But endoscopy is costly, invasive technique and

unpleasant procedure that some “patients at risk” would never

agree to undergo UGE because of the perceived discomfort. In

addition, it is unclear how often patients should be screened

endoscopically for varices. Therefore, the importance of non-

invasive predictors for early diagnosis of oesophageal varices

has emerged.

Many studies in this field were done using platelet

count, Insulin resistance, splenomegaly, bilirubinemia, PT,

platelet count/spleen diameter ratio and serum fibrosis markers

but their accuracy remains limited (Madhotra et al., 2002;

Thomopoulos et al., 2003; Burton et al., 2007; De

Franchis,2008; Eslam et al., 2013)

Glycated hemoglobin (HbA1c) and glycated albumin

(GA) are indexes of glycemic control in patients with diabetes

mellitus. HbA1c depends on the lifespan of erythrocytes which

is about 120 d. Glycated albumin correlates with the plasma

glucose levels during the past few weeks because the turnover

of albumin is about 20 d. Although the ratio of GA/HbA1c is

usually close to 3, In patients with chronic liver disease (CLD),





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hypersplenism shortens the lifespan of erythrocytes, leading to

lower HbA1c levels relative to the plasma glucose level. On the

other hand, the turnover periods of serum albumin in CLD

patients is prolonged as a compensatory mechanism for the

reduced production of albumin. Therefore, the GA levels in CLD

patients are higher relative to the degree of glycaemia (Koga

and Kasayama, 2010)

Indeed, the GA/HbA1c ratio has been reported to be

associated with the histological stage of liver fibrosis and portal

hypertension in HCV-positive CLD and non-alcoholic

steatohepatitis (Bando et al., 2009; Aizawa et al., 2012;

Sakai et al., 2012; Bando et al., 2012) This study aimed to

determine the relation between (GA/HbA1c) ratio and the

oesophageal varices presence and its grading, in Egyptian

patients with liver cirrhosis.

PATIENTS AND METHODS:

This case-control study included 45 patients with liver cirrhosis

of any Child-Pugh grade attending the Gastroenterology-

Hepatology department and endoscopy unit of internal

medicine department at Ain Shams University Hospitals, and

included 15 (non-cirrhotic) patients as a control group in the

period from May 2014 to April 2015.

Subjects were divided into two groups:

Group I: included 45 patients with liver cirrhosis, diagnosed by

the laboratory, endoscopic and ultrasonographic finings. This

group was further subdivided into 3 subgroups according to the

grade of the O.Vs and subsequently the risk of bleeding:

Group I A: 15 patients with grade I to II oesophageal varices,

"low risk group".

Group I B: 15 patients with grade III to IV oesophageal

varices, "medium risk group".





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Group I C: 15 patients with oesophageal varices with red

signs, "high risk group".

Group II: 15 non-cirrhotic patients (as control).

Exclusion criteria: Diabetic patients, renal impairment,

previous history of upper GIT bleeding (Hematemesis &

melena) or any previous intervention for the oesophageal

varices, decrease RBCs life span like chronic haemolytic

anaemia, recent blood donation in recent three months, cases of

portal vein thrombosis and hepatocellular carcinoma.

All patients and controls were subjected to:

I. Full medical history taking and complete clinical

examination: With special stress on previous history

of chronic liver disease, symptoms of liver cell failure

such as (jaundice, bleeding and encephalopathy)

medical history of chronic disease as D.M. And

examination of liver and spleen size, ascites & signs of

liver cell failure as jaundice, palmar erythema and

encephalopathy.

II. Laboratory investigations: including Complete

blood count (CBC) and Erythrocyte sedimentation rate

(ESR), Liver function tests (aspartate

aminotransferase (AST), alanine aminotransferase

(ALT), serum albumin, total and direct bilirubin and

Alkaline phosphatase), Prothrombin Time (PT in

seconds), International Normalized Ratio (INR),

Fasting Blood Sugar (FBS), two hours post prandial

sugar, Renal function tests [Serum creatinine, Blood

Urea Nitrogen (BUN), urea]

III. Glycated albumin to glycated haemoglobin ratio:

Glycated albumin was measured by Sandwich ELISA

technique utilizing a commercial kit manufactured by

Glory Science. According to the manufacturer, the





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assay range is 0.5 to 250 %. Glycated hemoglobin,

however, was measured by an HPLC assay on Biorad

automated system. The assay is linear up to a

concentration of 10 %. Then the GA/HbA1c ratio was

calculated.

IV. Abdominal ultrasound: To detect Portal Vein

Diameter (PVD), liver span and spleen bipolar

longitudinal diameter & ascites and to exclude other

organomegaly, portal vein thrombosis or

hepatocellular carcinoma.

V. Upper Gastrointestinal Endoscopy: Performed

after written consent from patients under sedation to

determine the grade of esophageal varices and the

grade of Portal Hypertensive gastropathy:

- Grading of OVs was done according to Paquet

grading system (Paquet., 1982):

Grade I: Microcapillaries located in distal oesophagus or

oesophago-gastric junction.

Grade II: One or two small varices located in the distal

oesophagus.

Grade III: Medium-sized varices of any number.

Grade IV: Large-sized varices in any part of oesophagus.

Red colour signs: are red wale marks as

longitudinal red streaks on varices, Cherry

red spots, Hematocystic spots (raised discrete

red spots overlying varices that resemble

"blood blisters", Diffuse erythema denotes a

diffuse red colour of the varix. (Bosch et al.,

2003). (Kim et al., 1997)

- Grading of Portal Hypertensive Gastropathy

(PHG): was done according to Baveno grading

system (De Franchis R, on behalf of the Baveno

VI Faculty, 2015).





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Mild PHG: Fine pink speckling (scarlatina-

type rash), Superficial reddening Mosaic

pattern.

Severe PHG: Discrete red spots, Diffuse

hemorrhagic brown lesion

VI. Statistical analysis: The collected data was revised,

coded, tabulated and introduced to a PC using

Statistical Package for Social Science (SPSS 15.0.1 for

windows; SPSS Inc, Chicago, IL, 2001). Data were

presented and suitable analysis was done according to

the type of data obtained for each parameter.

Descriptive statistics

Mean, Standard deviation (± SD) and range for parametric

numerical data, Frequency and percentage of non-numerical

data.

Analytical statistics

Student t- Test was used to assess the statistical significance of

the difference between two study group means. Analysis of

variance (ANOVA) test is used to determine the statistically

significant differences between the means of three or more

independent (unrelated) groups. Correlation analysis: Pearson's

correlation coefficient (r) test was used to assess the strength of

association between two quantitative variables. The correlation

coefficient defines the strength and direction of the linear

relationship between two variables.

P- value (propability test): to assess the level of significance

P>0.05=Non-significant (NS).

P≤0.05: Significant (S).

P≤0.01: Highly significant (HS).





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RESULTS:

This study was conducted on 45 patients with liver cirrhosis

and oesophageal varices recruited from the Gastroenterology-

Hepatology department and endoscopy unit of internal

medicine department at Ain Shams University Hospitals in the

period from May 2014 to April 2015.They were (24 male & 21

female), their age ranged from 40 to 65 years old and mean ±

SD of 54.4 ± 5.79 years old. Fifteen non-cirrhotic patients of

matching age and sex, attending the department for other

complains were included as a control group.

Comparison between both patients and control groups:

showed nearly a highly significant difference regarding

different laboratory investigations (table 1). Also, comparing

the two groups regarding the ultrasound findings, there was a

highly significant difference as regards the splenic diameter

and the portal vein diameter (table 2). Comparison between

patients and control as regard Endoscopic results showed that

the mean ± SD of the number of O.V cords was (3 ± 0.8), PHG

was mild in 22 (48.9%) and severe in 17 (37.8%) of patients

group.

Table (1): Comparison between patients and control as regard

laboratory data.

Patients Control

Mean ± SD Mean ± SD t-test p-value Sig.

Hb (g/dL) 9.71 ± 0.60 10.83 ± 0.48 -6.474 <0.001 HS

Plt (X103/UL) 140.36 ± 53.98 377.27 ± 30.30 -16.114 <0.001 HS

AST (U/L) 53.93 ± 5.31 31.20 ± 7.86 12.656 <0.001 HS

ALT (U/L) 57.33 ± 6.46 30.40 ± 9.27 12.479 <0.001 HS

Alk.P (IU/L) 83.16 ± 26.40 64.93 ± 13.73 2.550 0.013 S

T.Bil (mg/dl) 1.15 ± 0.16 0.85 ± 0.09 6.548 <0.001 HS

D.Bil (mg/dl) 0.65 ± 0.09 0.45 ± 0.05 7.706 <0.001 HS

S.Alb (g/dl) 3.21 ± 0.48 4.43 ± 0.34 -9.032 <0.001 HS

PT (Sec) 17.89 ± 3.19 13.87 ± 1.06 4.769 <0.001 HS

INR 3.88 ± 16.64 1.02 ± 0.04 0.661 0.511 NS

Hb=haemoglobin, Plt=platelets, ALT=Alanine aminotransferase,

AST=Aspartate aminotransferase, Alk.P=alkaline phosphatase, T.Bil=Total





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Bilirubin, D.Bil =Direct Bilirubin, S.alb=serum albumin, PT=prothrombin

time, INR=international normalized ratio.

Table (2): Comparisons between patients and control as regard

Ultrasound examination.

patients

Mean ± SD

Control

Mean ± SD

t-test p-value Sig.

Liver span (cm) 14.33 ± 2.74 13.33 ± 1.05 1.375 0.175 NS

Splenic diameter (cm) 17.58 ± 1.41 10.67± 1.40 16.512 <0.001 HS

PVD (mm) 16.5 ± 2.43 9.33 ±1.50 12.853 <0.001 HS

Ascites* 15 (33.34 %) - - - -

*is represented as the number (and %) of patients who had ascites.

Comparison between patient and control groups: there was a

highly significant (HS) difference (p<0.001) as regard glycated

albumin level (being higher in the patients group), comparing

the glycated Hb levels showed a highly significant difference

between both groups (being lower in the patients group), and by

comparing the GA/HbA1c ratio there was a highly significant

statistical difference between both groups being higher in the

patients group (GA/HbA1c ratio =3.03±0.11 in the control

group, and equals 4.3±0.57 in the patients group) (table3).

Table (3): Comparison between patients and control as regard

Glycated Alb, Glycated Hb and the GA/HbA1c ratio:

Patients

(Mean ± SD)

Control

(Mean ± SD)

t-test p-value Sig.

Glycated Alb (%) 15.86 ± 0.84 13.35 ± 0.42 11.006 <0.001 HS

Glycated Hb (%). 3.67 ± 0.34 4.37 ± 0.20 -7.601 <0.001 HS

GA/HbA1c Ratio 4.3 ± 0.57 3.03 ± 0.11 9.046 <0.001 HS

Comparison between the three patients’ subgroups: regarding

the laboratory investigations showed that there was a highly

significant difference as regards (Hb, Platelet count, Alkaline

phosphatase, total Bilirubin, serum Albumin and PT), also

there was a significant difference by comparing AST, ALT and

direct Bilirubin levels. And there was a highly significant

difference between different patient subgroups by comparing





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the liver span, splenic diameter and Portal vein diameter, and a

significant difference as regard presence of ascites (table 4).

There was a highly significant difference as regards grade of

O.Vs and P.H.G (table 5).

Table (4): comparison between different cirrhotic patients’ subgroups

as regard laboratory data and U/S findings:

Group Ia Group

Ib

Group Ic ANOVA

(Mean ±

SD)

(Mean ±

SD)

(Mean ±

SD)

F P Sig

.

Hb (g/dl) 10.1 ± 0.49 9.79 ±

0.45

9.19 ± 0.45 16.348 <0.00

1

HS

Plt (X103/UL) 196.87 ±

51.87

129.47 ±

22.52

94.73 ±

13.45

35.924 <0.00

1

HS

AST (U/L) 52.00 ± 4.87 52.87 ±

5.79

56.93 ± 4.06 4.233 0.021 S

ALT (U/L) 54.73 ± 5.43 55.40 ±

6.21

61.87 ± 5.46 7.138 0.002 S

Alk.P (IU/L) 64.07 ±

17.60

82.60 ±

30.50

102.80 ±

12.13

12.178 <0.00

1

HS

T.Bil (mg/dl) 1.03 ± 0.12 1.11 ±

0.14

1.30 ± 0.10 20.262 <0.00

1

HS

D.Bil. (mg/dl) 0.70± 0.08 0.61±

0.11

0.64 ± 0.07 3.724 0.032 S

S.Alb (g/dl) 3.70 ± 0.38 3.11 ±

0.35

2.83 ± 0.22 28.724 <0.00

1

HS

PT (sec) 14.93 ± 2.12 18.13 ±

1.77

20.60 ± 2.67 24.656 <0.00

1

HS

INR 1.19 ± 0.14 1.4 ±

0.18

1.57 ± 0.22 1.015 0.371 NS

Liver span (cm) 17.73±1.91 13.00±1.

20

12.47±0.52 70.913 <0.00

1

HS

Splenic

diameter(cm)

16.27±0.70 17.73±0.

96

19.87±0.92 65.333 <0.00

1

HS

PVD (mm) 15.40±1.12 16.13±0.

83

16.5±1.19 100.00

3

<0.00

1

HS

Ascites* 0 (0%) 6 (40%) 9 (60%) 5.904 0.015 S

Hb=haemoglobin, Plt=platelets, ALT=Alanine aminotransferase, AST=Aspartate

aminotransferase, Alk.P=alkaline phosphatase, T.Bil=Total Bilirubin, D.Bil =Direct

Bilirubin, S.alb=serum albumin, PT=prothrombin time, INR=international normalized

ratio.

*is represented as the number (and %) of patients who had ascites.





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Table (5): comparison between different cirrhotic patients’ subgroups

as regard Endoscopic findings:

Endoscopy:

Group Ia Group Ib Group Ic ANOVA

F P Sig.

OV

No of cords (mean±SD)

2.73 ± 0.88

2.93 ± 0.70

3.40 ± 0.63

3.142

0.053

NS

P.H.G

Mild [No (%)]

Severe [No (%)]

10 (66.67%)

9 (60%)

2 (13.33%)

26.266

<0.001

HS

0 (0%) 5 (33.4%) 13 (86.67%)

Comparing the glycated albumin values between the three

patients’ subgroups (table 6) showed a highly significant

difference, being highest in group Ic “the high risk “group

(mean ± SD is 16.64 ± 0.58 %). in contrast, the values of the

glycated Hb (HbA1c) were of the lowest values in the high-risk

group and there was a highly significant difference when

comparing the three groups. The GA/HbA1c ratio was

increasing with the increasing risk of bleeding, showing the

lowest value in the “low risk” group (3.77 ± 0.24) and the

highest value in the “high risk” group (5.03 ± 0.22).

Tables (6): comparison between different patients subgroups as

regard Glycated Alb, Glycated Hb and The GA/HbA1c ratio.

Group Ia Group Ib Group Ic ANOVA

Mean ± SD Mean ±SD Mean ±SD p Sig.

Glycated Alb (%) 14.97 ±0.51 15.96 ±0.37 16.64 ±0.58 43.327 <0.001 HS

Glycated Hb (%). 3.99 ±0.19 3.71 ±0.16 3.31 ±0.20 50.538 <0.001 HS

GA/HbA1c Ratio 3.77 ±0.24 4.31 ±0.22 5.03 ±0.22 118.877 <0.001 HS

Correlating the GA/HbA1c ratio with other laboratory, U/S

and endoscopic findings (table 7) showed that there was a

significant positive correlation between the GA/HbA1c ratio and

(the number of variceal cords and the PVD) in all subgroups. As

expected, the ratio also correlated with the Hb and serum

albumin levels. But non-significant correlation with (AST, ALT,

Alk.P, total Bilirubin, direct bilirubin, liver span and splenic

diameter). Platelet count was highly negatively correlated to





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the AG/HBA1c ratio in the “High risk” group only. PT only

correlated to the ratio in the low risk group.

Table (7): Correlation between the GA/HbA1c ratio and the Other

Studied Parameters in the three patients’ subgroups

All parameters Group Ia Group Ib Group Ic

r p-value r p-value R p-value

Age 0.434 0.106 0.035 0.901 0.277 0.318

Hb -0.550 0.034* -0.626 0.013* -0.588 0.021*

Plt -0.072 0.798 -0.097 0.732 -0.693 0.004*

AST 0.364 0.183 -0.175 0.532 0.362 0.184

ALT 0.352 0.199 0.114 0.685 0.466 0.080

ALK.P 0.463 0.083 0.347 0.205 0.208 0.457

T.Bil. 0.215 0.442 0.062 0.826 0.033 0.907

D.Bil 0.249 0.372 -0.038 0.892 -0.315 0.252

S.Alb -0.532 0.041* -0.315 0.253 -0.745 0.001*

PT 0.561 0.029* 0.357 0.191 0.485 0.067

INR 0.619 0.014* -0.139 0.622 0.579 0.024*

Liver span -0.164 0.559 -0.268 0.335 -0.249 0.370

Splenic diameter -0.426 0.113 0.028 0.921 0.200 0.474

PVD (mm) 0.582 0.023* -0.584 0.022* 0.652 0.008*

Endoscopy

No of cords 0.871 <0.001** 0.379 0.032* 0.682 0.005*

Hb=haemoglobin, Plt=platelets, ALT=Alanine aminotransferase, AST=Aspartate

aminotransferase, Alk.P=alkaline phosphatase, T.Bil=Total Bilirubin, D.Bil =Direct

Bilirubin, S.alb=serum albumin, PT=prothrombin time, INR=international normalized

ratio.

*significant difference, **highly significant difference.

DISCUSSION:

Non-invasive tests of liver fibrosis have revolutionized the

management of chronic liver diseases. Compared with routine

clinical assessments, the non-invasive tests allow more

confident diagnosis of cirrhosis and can also reflect the severity

of cirrhosis and/or portal hypertension. They can therefore be

used to better select patients for varices screening and to allow

cost saving by reducing the number of endoscopies.

The Transient Elastograghy combined with platelet

count is the only recommended technique by The Baveno VI

panel (DeFranchis, 2015) to diagnose portal hypertension.





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However, researchers continue to look for an ideal (accurate,

simple, inexpensive and easily reproducible) method.

A new biomarker based on a combination of metabolic

parameters that includes the GA/HbAc ratio had been proposed

as a useful tool for evaluating the risk of presence of

oesophageal varices in patients with liver cirrhosis.

In this study, we aimed to assess the role of GA/HbA1c

ratio as a screening test for the presence of oesophageal varices

in Egyptian patients with liver cirrhosis. The second aim was to

examine the possible correlation between the GA/HbA1c ratio

and the grade of O.Vs.

We found that there was a highly significant difference

between patients and control as regards the Glycated Albumin,

HbA1c and the GA/HbA1c ratio. as compared by mean values,

the GA/HbA1c ratio was (3.03) in controls and (4.37) in patients

group, suggesting that the increased (GA/HbA1c) ratio may be

considered as a predictor for presence of O.Vs. Furthermore, the

GA/HbA1c ratio was significantly higher in patients in the

“high risk varices group” as compared by mean value which was

increasing from group Ia (3.77) to group Ib (4.31) to group Ic

(5.03). There was a highly significant positive correlation

between the GA/HbA1c ratio and the grade of Oesophageal

varices suggesting that the increase of GA/HbA1c ratio is

associated with a higher grade of O.Vs and subsequently with

the risk of variceal bleeding and this was in agreement with

(Sakai et al., 2012).

Many previous studies (e.g. Madhotra et al. 2002;

Wang et al., 2012; Eslam et al., 2013) have documented good

predictive value of platelet count as a non-endoscopic variable

for the presence or absence of varices. In our study, there was a

highly significant difference between the three patients’

subgroups as regards the platelet count. In addition, there was

a highly significant negative correlation between the platelet

count and the GA/HbA1c ratio in the “high risk” group.





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Also, several studies have evaluated other blood tests to predict

varices such as and AST-to-platelet Index (Tafarel et al.,

2011; Colecchia et al., 2011; Morishita et al., 2014). Also,

Park et al., 2009 developed a simple risk score comprising

bilirubin and platelets to predict Hepatic vein pressure

Gradient (HVPG) and his results agreed with Procopet

etal.,2015. In the current study, there was a highly significant

difference between different patients subgroups as regard liver

function testes: (Platelet count, total Bilirubin, S. Albumin, PT)

and also (Hb and Alkaline Phosphatase) were found to be better

in group Ia (low risk) and worst in group Ic (high risk O.Vs)

which suggested that there may be a relation between

progression of chronic liver disease and the degree of O.Vs and

this agrees with Tafarel et al (2011). Also there was a

significant difference between different patients subgroups as

regard (AST, ALT and direct Billirubin). (Chang et al., 2007)

agreed with our results that low serum albumin level and

prolonged prothrombin time were significant with the presence

of varices.

Many studies have adopted the ultrasound examination

findings as predictors to diagnose portal hypertension. In our

study, the PVD was highly significantly different in the three

patients’ subgroups. This goes in agreement with Hong et al.,

2009; and Cherian et al., 2011 who found that PVD was

significant with the presence of O.Vs. In addition, we found that

the GA/GHbA1c ratio was significantly correlated with the PVD

in all patients’ subgroups. Sharma and Aggarwal ,2007 in a

prospective study, observed that splenomegaly, increased liver

span and platelet count were the independent predictors for the

presence of large varices. In the current study, we also found

highly significant differences between the three patients’

subgroups regarding the liver span and the splenic bipolar

diameter values.





388

In conclusion, we describe a predictive model for assessing the

probability of the presence of O.Vs which can be used as an

initial screening tool in cirrhotic patients. So far, the available

data do not allow for the complete replacement of endoscopy in

OV screening, but may help in confirming the necessity of

endoscopy in those with suspected high risk of bleeding O.Vs.

Our findings indicate that the GA/HbA1c ratio predicts the

presence of oesophageal variceal and it can be considered in

prognostic models in patients with cirrhosis and portal

hypertension.

RECOMMENDATIONS:

Further prospective studies might be needed to find a cutoff

value of GA/GHba1c ratio and this might result in a

discriminating algorithm to predict which patients with

cirrhosis would benefit from early or regular endoscopy to

detect clinically significant varices. This cost effective

parameter may help identify patients with mild or no O.Vs who

may not need UGE to reduce costs and discomfort for these

patients and the burden on health system.

CONFLICT OF INTEREST: The authors declare that there is

no conflict of interests regarding the publication of this paper.

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Lastupdated: January2015.

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